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Histopathological regression after neoadjuvant docetaxel, oxaliplatin, fluorouracil, and leucovorin versus epirubicin, cisplatin, and fluorouracil or capecitabine in patients with resectable gastric or gastro-oesophageal junction adenocarcinoma(FLOT4-AIO)

Al-Batran SE, Hofheinz RD, Pauligk C, Kopp HG, Haag GM, Luley KB, et al.

Lancet Oncol. 2016 Dec;17(12):1697-1708.

Selected and commented by Dr Lizzy Smyth:

In this manuscript,  Al Batran et al. present the results of the German FLOT4-AIO study in which 300 patients with patients with resectable gastric cancer were treated with either three cycles of neoadjuvant ECX/ECF (epirubicin, cisplatin and 5-fluorouracil or capecitabine)  chemotherapy or four cycles of neoadjuvant FLOT (5-fluorouracil, leucovorin, oxaliplatin and docetaxel) chemotherapy.   The primary endpoint of this phase II component of the study was pathological complete response according to Becker criteria. The FLOT regimen was associated with statistically higher rates of pathological complete regression than ECX/ECF [16% vs 8%; p=0·02).   There were no significant differences in the proportion of patients with involved lymph nodes in the resection specimen (N1 or greater) between the arms of the trial.

These results are of interest, as higher rates of pathological response in the perioperative setting could translate into higher rates of curative surgery due to tumour downstaging. Indeed, more patients in the ECX than in the FLOT did not proceed to surgery (19% vs. 7%); in most cases this was due to detection of unresectable disease or metastases before surgery.    However, there was also an imbalance in the proportion of gastroesophageal junctional tumours in the ECX arm of the trial (52% vs 43%) which may have affected rates of surgical resection.     Chemotherapy related toxicities were as expected for these regimens; ECX was associated with higher rates of nausea and vomiting, whereas FLOT was associated with higher rates of significant neutropenia and neuropathy.    Dose modifications were also similar between the two treatment arms (42% ECX vs 38% FLOT), however chemotherapy discontinuation at the patients request was higher for patients treated with ECX/ECF (14% vs 8%).  

The real question regarding this study is whether improved rates of pathological response can translate into improvements in overall survival for patients with resectable gastroesophageal cancer.   It is not clear that pathological response rates are an independent predictor of overall survival, as other factors, in particular lymph node metastases, may be more important.    This was recently demonstrated in a retrospective analysis of the MAGIC trial in which pathological response to chemotherapy was a predictor of overall survival on univariate analysis, but when assessed in conjunction with lymph node status, did not retain its predictive value (Smyth et al, JCO 2016).   This means that even if FLOT improves pathological response in the primary tumour, if the proportion of patients with metastatic lymph nodes is not also decreased, then overall survival may not improve for these patients.    The lack of impact of pathological tumour regression on overall survival is also supported by the results of the OE05 study, in which intensification of perioperative chemotherapy (four cycles of ECX compared to two cycles of CF) improved rates of primary tumour pathological response but did not improve overall survival (Cunningham ASCO 2015).

Current international guidelines recommend cisplatin and fluoropyrimidine based perioperative chemotherapy for patients with resectable gastric cancer (ESMO 2016),  use of epirubicin containing regimens is also appropriate for patients with good performance status.    At the moment, as no survival data is available for perioperative FLOT, use of this regimen cannot be recommended in the perioperative setting.    However, the results of the FLOT 4 trial are encouraging, and we look forward to reviewing the overall survival results of the trial when available.

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